Tuberous Sclerosis Complex

Clinical characteristics.

Tuberous sclerosis complex (TSC) involves abnormalities of the skin (hypomelanotic macules, confetti skin lesions, facial angiofibromas, shagreen patches, fibrous cephalic plaques, ungual fibromas); brain (subependymal nodules, cortical dysplasias, and subependymal giant cell astrocytomas [SEGAs], seizures, intellectual disability / developmental delay, psychiatric illness); kidney (angiomyolipomas, cysts, renal cell carcinomas); heart (rhabdomyomas, arrhythmias); and lungs (lymphangioleiomyomatosis [LAM], multifocal micronodular pneumonocyte hyperplasia). Central nervous system tumors are the leading cause of morbidity and mortality; renal disease is the second leading cause of early death.

Diagnosis/testing.

The diagnosis of TSC is established in a proband with one of the following:

• Two major clinical features
• One major clinical feature and two or more minor features
• Identification of a heterozygous pathogenic variant in TSC1 or TSC2 by molecular genetic testing

Management.

Treatment of manifestations: For enlarging SEGAs: mTOR inhibitors; neurosurgery when size causes life-threatening neurologic symptoms. For seizures: vigabatrin and other antiepileptic drugs, and on occasion, epilepsy surgery. For renal angiomyolipomas >4 cm, or >3 cm and growing rapidly: mTOR inhibitors are the recommended first line of therapy with secondary therapy options being embolization, renal sparing surgery, or ablative therapy. For facial angiofibromas: topical mTOR inhibitors. For symptomatic cardiac rhabdomyomas: surgical intervention or consideration of mTOR inhibitor therapy. For LAM: mTOR inhibitors.

Prevention of secondary complications: For those on vigabatrin therapy, vision testing within four weeks of therapy initiation, at three-month intervals while on treatment, and three to six months after treatment is discontinued.

Surveillance: Brain MRI every one to three years in asymptomatic individuals with TSC younger than age 25 years to monitor for new occurrence of SEGAs; those with asymptomatic SEGA in childhood should continue to be imaged periodically in adulthood; for those with large or growing SEGA or SEGA causing ventricular enlargement, more frequent brain MRIs as deemed clinically appropriate; screening for TSC-associated neuropsychiatric disorder (TAND) at least annually with comprehensive formal evaluation for TAND at key developmental time points; EEG in individuals with known or suspected seizure activity; MRI of the abdomen to assess for progression of angiomyolipoma and renal cystic disease every one to three years; assess renal function (glomerular filtration rate and blood pressure) at least annually; echocardiogram every one to three years in asymptomatic infants and children with cardiac rhabdomyomas until regression is documented; clinical screening for LAM symptoms (exertional dyspnea and shortness of breath) at each clinic visit in women older than age 18 years or those who report respiratory symptoms; high-resolution computed tomography (HRCT) every five to ten years in asymptomatic individuals at risk for LAM (adult females age >18 years) even when there are no signs of LAM on baseline examination; annual pulmonary function testing and HRCT every two to three years for individuals with lung cysts detected by HRCT; annual dermatologic examination; dental examination every six months; annual ophthalmology evaluation in those with previously identified ophthalmologic lesions or vision symptoms.

Agents/circumstances to avoid: Smoking; estrogen use; nephrectomy.

Evaluation of relatives at risk: Identifying affected relatives enables monitoring for early detection of problems associated with TSC, which leads to earlier treatment and better outcomes.

Genetic counseling.

TSC is inherited in an autosomal dominant manner. Two thirds of affected individuals have TSC as the result of a de novo pathogenic variant. The offspring of an affected individual are at a 50% risk of inheriting the pathogenic variant. If the pathogenic variant has been identified in an affected family member, prenatal testing for pregnancies at increased risk and preimplantation genetic testing are possible.

Suggestive Findings

Tuberous sclerosis complex (TSC) should be suspected in individuals with either one major clinical feature or two or more minor features, as listed below.

Major features

• Angiofibromas (≥3) or fibrous cephalic plaque
• Cardiac rhabdomyoma
• Cortical dysplasias, including tubers and cerebral white matter migration lines
• Hypomelanotic macules (3 to >5 mm in diameter)
• Lymphangioleiomyomatosis (LAM) (see *Note)
• Multiple retinal nodular hamartomas
• Renal angiomyolipoma (see *Note)
• Shagreen patch
• Subependymal giant cell astrocytoma (SEGA)
• Subependymal nodules (SENs)
• Ungual fibromas (≥2)

Minor features

• "Confetti" skin lesions (numerous 1- to 3-mm hypopigmented macules scattered over regions of the body such as the arms and legs)
• Dental enamel pits (>3)
• Intraoral fibromas (≥2)
• Multiple renal cysts
• Nonrenal hamartomas
• Retinal achromic patch

Establishing the Diagnosis

Clinical diagnostic criteria for TSC have been revised [Northrup et al 2013] to take into account the results of molecular genetic testing.

A definite diagnosis of TSC is established in a proband with EITHER of the following:

• Two major features (see *Note) or one major feature with two or more minor features
• Identification of a heterozygous pathogenic variant in either TSC1 or TSC2 by molecular genetic testing (see Table 1)

*Note: The combination of LAM and angiomyolipomas without other features does not meet the clinical diagnostic criteria for a definite diagnosis.

Molecular genetic testing approaches can include concurrent gene testing or use of a multigene panel:

• Concurrent gene testing. Perform sequence analysis and gene-targeted deletion/duplication analysis of TSC1 and TSC2.
  Note: If no pathogenic variant is identified, somatic mosaicism for a pathogenic variant should be considered [Qin et al 2010; Nellist et al 2015; Authors, personal observation]. For more information on somatic mosaicism as a cause of TSC click here (pdf).
• A multigene panel that includes TSC1, TSC2 and other genes of interest (see Differential Diagnosis) may be considered to identify the genetic cause when the diagnosis of TSC is less certain in order to limit cost and limit identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests. For this disorder a multigene panel that also includes deletion/duplication analysis is recommended (see Table 1).
  For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with tuberous sclerosis complex (TSC), the evaluations summarized in Table 2 (if not performed as part of the evaluation that led to the diagnosis) are recommended by the International Tuberous Sclerosis Consensus Conference [Northrup et al 2013] (full text).

Treatment of Manifestations

Subependymal giant cell astrocytomas (SEGAs). Early identification of an enlarging giant cell astrocytoma permits medical therapy with mTOR inhibitors [Krueger et al 2010], which may obviate the need for neurosurgical intervention in many individuals. However, neurosurgery may still be indicated when the size of the SEGA causes life-threatening neurologic symptoms.

Seizures. Early control of seizures is thought to prevent subsequent epileptic encephalopathy and reduce cognitive behavioral consequences [Bombardieri et al 2010]. The efficacy of different treatments for infantile spasms varies among individuals; however a retrospective review found that vigabatrin controlled infantile spasms in 73% of children with TSC [Camposano et al 2008] (see Prevention of Secondary Complications). An ongoing study (see clinicaltrials.gov) is prospectively investigating the effect of early vigabatrin treatment on developmental outcomes in babies with TSC-associated infantile spasms.

The seizures in TSC may be resistant to polydrug therapy with anticonvulsants. A number of small studies have reported excellent results after epilepsy surgery.

• Jarrar et al [2004] found that unifocal-onset seizures and mild to no developmental delay at the time of surgery predict an excellent long-term outcome.
• Romanelli et al [2004] discussed the use of electroencephalographic techniques, functional neuroimaging, and invasive cortical mapping to aid the surgeon in evaluating options for surgical resection in individuals with TSC who have multifocal epileptogenic zones.
• Kagawa et al [2005] found that increased radiolabeled alpha-methyl-L-tryptophan uptake on PET scans identifies epileptogenic tubers with 83% accuracy, thus enhancing successful epilepsy surgery.
• Weiner et al [2006] used a three-staged bilateral surgical approach in 22 persons with TSC. They suggest that this approach can help identify both primary and secondary epileptogenic zones in young persons with multiple tubers.

Initial case reports suggested a potential for mTOR inhibitors to help in the treatment of intractable epilepsy in individuals with TSC [Krueger et al 2013b]. The EXIST-3 clinical trial [French et al 2016] confirmed the benefit of these therapies; EXIST-3 received FDA approval (4/10/18) as adjunctive treatment of TSC-associated partial-onset seizures.

Renal angiomyolipoma

• For asymptomatic, growing angiomyolipoma measuring >4 cm in diameter or >3 cm and growing rapidly, treatment with an mTOR inhibitor is currently recommended as the most effective first-line therapy in the short term [Davies et al 2011, Bissler et al 2013]. The demonstrated tolerability to date is far preferable to the renal damage caused by angiomyolipoma progression or surgical and embolitic/ablative therapies, though studies are still needed to confirm long-term benefits and safety [Krueger et al 2013b].
• Selective embolization followed by corticosteroids, kidney-sparing resection, or ablative therapy for exophytic lesions is acceptable second-line therapy for asymptomatic angiomyolipomas [Bissler et al 2002].
• For acute hemorrhage, embolization followed by corticosteroids is more appropriate [Mourikis et al 1999]. Nephrectomy is to be avoided because of the high incidence of complications and increased risk for future renal insufficiency and end-stage renal failure, and the poor prognosis that results from chronic kidney disease.

Facial angiofibromas. Topical mTOR inhibitor formulations have been shown to be efficacious in the treatment of facial angiofibromas.

Cardiac rhabdomyomas. Previous standard of care for the treatment of newborns with cardiac rhabdomyomas resulting in life-threatening complications (i.e., outflow tract obstruction) was surgery. There have now been several reports of off-label use of mTOR inhibitors to treat cardiac rhabdomyomas in infants with TSC with encouraging results [Dogan et al 2015, Goyer et al 2015, Mlczoch et al 2015]. These reports indicate that mTOR inhibitors may be a better alternative than surgery for clinically significant cardiac rhabdomyomas.

LAM. Trials have demonstrated efficacy of mTOR inhibitors for LAM [McCormack et al 2011]. The FDA approved use of mTOR inhibitors for treatment of the lung issues in people with TSC (5/28/15). Official guidelines for diagnosis and management of LAM have been published [McCormack et al 2016, Gupta et al 2017].

Prevention of Secondary Complications

For those on vigabatrin therapy, vision testing is recommended within four weeks of treatment initiation, every three months during therapy, and three to six months after treatment is discontinued because of the risk for peripheral visual field restriction (SABRIL prescribing information).

Surveillance

The following routine monitoring is recommended for individuals with TSC (adapted from Krueger et al [2013a], Table 3).

Central nervous system

• Obtain MRI of the brain every one to three years in asymptomatic (i.e., having no CNS-related symptoms) individuals with TSC younger than age 25 years to monitor for new occurrence of SEGA. Those with asymptomatic SEGA in childhood should continue to be imaged periodically as adults to ensure that there is no growth.
• In affected individuals with large or growing SEGA causing ventricular enlargement who are still asymptomatic, brain MRI scans should be performed more frequently and these individuals and their families should be educated regarding the potential for new symptoms.
• Perform screening for TAND features at least annually. Perform comprehensive formal evaluation for TAND at key developmental points: infancy (0-3 years), preschool (3-6 years), pre-middle school (6-9 years), adolescence (12-16 years), early adulthood (18-25 years), and as needed thereafter.
• Obtain routine EEG in individuals with known or suspected seizure activity. The frequency of routine EEG should be determined by clinical need.

Renal

• Obtain MRI of the abdomen to assess for progression of angiomyolipomas and renal cystic disease every one to three years throughout the lifetime of the affected individual.
• Assess renal function (including determination of GFR) and blood pressure at least annually.

Cardiac

• In asymptomatic infants and children with documented cardiac rhabdomyomas, obtain an echocardiogram every one to three years until regression of the cardiac rhabdomyomas is documented.
• More frequent or advanced diagnostic assessment may be required for symptomatic individuals.

Pulmonary

• Perform clinical screening (targeted history) for LAM symptoms including exertional dyspnea and shortness of breath at each clinic visit for women older than age 18 years or those who report respiratory symptoms. Counseling regarding smoking risk and estrogen use should be reviewed at each clinic visit for individuals at risk for LAM.
• Obtain a high-resolution computed tomography (HCRT) of the lungs every five to ten years in asymptomatic individuals at risk for LAM who have no evidence of lung cysts on baseline HRCT. Individuals with lung cysts detected on HRCT should have annual pulmonary function testing (pulmonary function test and 6-minute walk) and HRCT every two to three years.

Skin. Perform detailed clinical dermatologic inspection/exam annually.

Dental. Perform detailed clinical dental inspection/exam at minimum every six months and panoramic radiographs by age seven years, if not performed previously.

Ophthalmologic. Perform annual ophthalmologic evaluation in affected individuals with previously identified ophthalmologic lesions or vision symptoms at the baseline evaluation.

Agents/Circumstances to Avoid

Avoid the following:

• Smoking
• Estrogen use in adolescent and adult females
• Nephrectomy (see Treatment of Manifestations, Renal angiomyolipoma)

Evaluation of Relatives at Risk

It is appropriate to evaluate apparently asymptomatic older and younger at-risk relatives of an affected individual in order to identify as early as possible those who would benefit from surveillance and early treatment. Evaluations can include:

• Molecular genetic testing if the pathogenic variant in the family is known;
• If the pathogenic variant in the family is not known, physical examination and imaging studies (skin examination, retinal examination, brain imaging, and renal ultrasound examination) to assess for the clinical features of TSC (see Diagnosis).

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

In general, women with epilepsy or a seizure disorder from any cause are at greater risk for mortality during pregnancy than pregnant women without a seizure disorder; use of antiepileptic medication during pregnancy reduces this risk. However, exposure to antiepileptic medication may increase the risk for adverse fetal outcome (depending on the drug used, the dose, and the stage of pregnancy at which medication is taken). Nevertheless, the risk of an adverse outcome to the fetus from antiepileptic medication exposure is often less than that associated with exposure to an untreated maternal seizure disorder. Therefore, use of antiepileptic medication to treat a maternal seizure disorder during pregnancy is typically recommended. Discussion of the risks and benefits of using a given antiepileptic drug during pregnancy should ideally take place prior to conception. Transitioning to a lower-risk medication prior to pregnancy may be possible [Sarma et al 2016].

See MotherToBaby for more information on medication use during pregnancy.

Therapies Under Investigation

Many clinical trials are assessing the effect of drug therapy on the manifestations of TSC (see ClinicalTrials.gov).

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for information on clinical studies for a wide range of diseases and conditions.